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Activation of the A₃ Adenosine Receptor Suppresses Superoxide Production and Chemotaxis of Mouse Bone Marrow Neutrophils

Department of Pharmacology and Toxicology and the Cardiovascular Center, Medical College of Wisconsin, Milwaukee, Wisconsin

Adenosine is formed in injured/ischemic tissues, where it suppresses the actions of essentially all cells of the immune system. Most of the anti-inflammatory actions of adenosine have been attributed to signaling through the G_s protein-coupled A_2A adenosine receptor (AR). Here, we report that the A₃AR is highly expressed in murine neutrophils isolated from bone marrow. Selective activation of the A₃AR with (2S,3S,4R,5R)-3-amino-5-[6-(2,5-dichlorobenzylamino)purin-9-yl]-4-hydroxytetrahydrofuran-2-carboxylic acid methylamide (CP-532,903) potently inhibited mouse bone marrow neutrophil superoxide generation and chemotaxis induced by various activating agents. The selectivity of CP-532,903 was confirmed in assays using neutrophils obtained from A_2AAR and A₃AR gene "knockout" mice. In a model of thioglycollate-induced inflammation, treating mice with CP-532,903 inhibited recruitment of leukocytes into the peritoneum by specifically activating the A₃AR. Collectively, our findings support the theory that the A₃AR contributes to the anti-inflammatory actions of adenosine on neutrophils and provide a potential mechanistic explanation for the efficacy of A₃AR agonists in animal models of inflammation (i.e., inhibition of neutrophil-mediated tissue injury).

Address correspondence to: Dr. John A. Auchampach, Department of Pharmacology and Cardiovascular Center, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226. E-mail: jauchamp{at}mcw.edu